On Mar. 14, 1960 Dr. Samuel Natelson, the inventor herein filed U.S. patent application Ser. No. 14,894, entitled "Automatic Chemical Analyzer". This application issued as U.S. Pat. No. 3,036,893 on May 29, 1962. This patent describes an arrangement for chemical analysis using three tapes or layers, both terms being synonymous terms. The sample was placed on a sample receiving tape to hold and evenly spread the sample. This sample receiving tape or layer was in contact with an intermediate porous tape designed to filter off unwanted components and to produce an even stain on a third test tape. The reason for the intermediate porous tape is described at length in the aforesaid U.S. Pat. No. 3,036,893. This patent established certain principles for the success of a layered tape system of chemical analysis.
1. The sample had to be spread evenly on the sample receiving tape. Since diffusion is too slow, capillarity had to be used to cause rapid spreading. This was done by paper or cloth. It was also established that the spread needed to be controlled since the same volume of serum and water did not spread to the same area. Confinement of the spread was recommended and explained in the aforesaid patent. PA1 2. The porous tape could use pores which can be seen under a microscope, as in bacterial filters with parchment, or submicroscopic pores as in cellophane. PA1 3. The sample receiving tape and test tape could be backed with plastic so as to provide support. PA1 4. The tapes or layers could be assembled in a continuous system, in the form of continuous tapes for the sequential analysis of different specimens. PA1 5. The system was flexible since numerous tests could be performed with the system such as glucose, amino acid nitrogen, calcium, magnesium, protein, total lipids, and radioactive inorganic iodine. Under proper conditions, this type of test can be adapted for radio-immunoassay. PA1 6. The system also taught the separation of tapes and the reading of the colored spots on the test tape by means of a densitometer or spectrophotometer, or, where radioactivity was present, by a gamma counter or scintillation counter. PA1 7. Methods were described for carrying out reactions at elevated temperatures and for automatically adding a sample. PA1 8. The use of non-grainy paper in the "test" tape for even spreading. PA1 9. The simultaneous administration of specimens to a multi-layered test system for analysis.
A continuation application of U.S. Pat. No. 3,036,893 introduced for the first time the concept of simultaneous analysis of specimens on a layered system containing a sample receiving tape, a porous tape, and a reagent tape. This continuation application issued as U.S. Pat. No. 3,216,804. In this system, a reagent was added to a large circle of filter paper. This was covered with a circle of cellophane, as the porous tape, and finally a circle of filter paper (liquid receiving tape) was placed on top to receive the specimen. The samples or specimens were added simultaneously from capillary tubes containing the samples to be analyzed. In addition this patent contained a description for the preparation of "non-grainy paper", for the even spreading of the specimen. The tapes were in the form of large filter papers and the samples were disposed in a circle near the outer perimeter. U.S. Pat. Nos. 3,216,804 and 3,036,893 demonstrated completely automated systems.
The advances made in U.S. Pat. No. 3,216,804 were as follows:
A divisional application of U.S. Pat. No. 3,036,893 issued as U.S. Pat. No. 3,261.668. This patent covered three flatstrip mediums, one being absorbant and designed to receive a sample, the second being porous to water and proteins but impervious to substances with a molecular weight higher than proteins, e.g., erythrocytes, and finally a test medium which was the third tape. The patent also provided for an impervious backing to the tapes, for confined spots, and for reagents to be contained in the test tape for analysis. Thus, U.S. Pat. No. 3,261,668 provided for the general tape system regardless of the composition of the tapes, provided that they had the property of absorbancy and porosity as required by the basic patent. The porosity of the intermediate tape could vary, but was such as to permit the passage of molecules of a size up to and including proteins, but not larger particles such as cells. This patent also introduced the concept of individual samples being set up for a particular test so that the operator could add the specimen to the receiving layer which was an integral part of a pad. This pad had upper and lower plastic covers and three tapes all encased in a plastic cover. The operator removed the cover and placed the sample on the sample receiving tape. The pad was closed and placed in a press plate for a fixed period of time. The sample passed to the test tape through the porous tape. The stain formed on the test tape was then read. The operator could keep a stock of different pads, one for each test, ready at any time for rapid analysis. This pad arrangement performs simple, but diverse tests required for the usual tests required by a small hospital laboratory or a physician's laboratory. While U.S. Pat. No. 3,261,688 recommended turning the upper tape down, so that the side to which the sample was applied faced the porous tape, it also shows that this was not essential and the desired component in the sample would pass through to the reagent tape and that many tests could be performed without moving the upper tape. This system also permitted the analysis of several samples or standards simultaneously.
Subsequently, several other U.S. patents were granted in the name of Samuel Natelson relating to automated chemical analysis systems, for laboratory and physician's use. These include U.S. Pat. Nos. 3,260,413; 3,368,872; 3,502,438; 3,219,416, and 3,502,438.
In U.S. Pat. No. 3,502,438, the inventor describes a system for moving and separating a multi-tape system for analysis. This system shows the method of reading the spot produced on the test tape by fluorescence or transmission. The patent also shows a method of reading a blank area by transmission, to be subtracted from the reading of the absorbance of the spot where the color has developed. Thus, it shows the analysis by means of a dual light beam system.
In U.S. Pat. No. 3,368,872 an instrument is described for moving the porous and test tape, bonded together, the test tape containing an impregnated reagent. Means are provided for emptying capillary tubes on a moving porous tape so that the component to be analyzed will diffuse through to the test tape for analysis. This system is intended for sequential analysis. In U.S. Pat. No. 3,915,652 the present inventor describes an improved method for adding specimens from capillary tubes on to a tape arrangement for analysis. This arrangement is especially useful in implementing one of the objects of the present invention.
Another apparatus which is useful in connection with the present inventive concept is described in the Samuel Natelson U.S. Pat. No. 4,004,150. This patent describes the use of a scanning wheel in evaluating the light intensity emitted from spots either by transmission, reflection or fluorescence. The spots in an array can be scanned electronically as with a television camera, the signals being discriminated and evaluated by a computer.
Some of the foregoing techniques as well as other inovations are described by Samuel Natelson in MICROCHEMICAL JOURNAL, Volume 13, Number 3, September 1968, pages 433-458 entitled: AUTOMATIC ANALYSIS OF MICROSAMPLES CONTAINED IN CAPILLARIES WITH A MICROSAMPLE DISPENSER.
Other technicians entering the field have also obtained patents, e.g., U.S. Pat. No. 3,992,158. In this patent, the flat strip medium designed to receive a sample is called the "spreading layer". Just as the sample receiving tape of Samuel Natelson spreads the sample by capillarity, a similar result is obtained by using various powders such as diatomaceous earth, titanium dioxide or glass beads to obtain capillarity for the rapid spreading required. The porous strip medium, intermediate the other two layers designed to filter out unwanted components is described in this patent as the filtering layer. The flat strip medium designed to carry the reagent, is called the reagent layer. The supports for the system correspond to those described in the aforementioned Samuel Natelson U.S. patents. A reflecting layer is provided. This feature is inherent in the construction described in the aforementioned Samuel Natelson patents since the filter paper is a reflecting medium which is also translucent. The porous tape described by Samuel Natelson in his patents, which has pores of a size which will not allow protein to pass through, as in the Samuel Natelson U.S. Pat. No. 3,261,668 is called a dialysis layer in U.S. Pat. No. 3,992,158.
However, none of the aforementioned U.S. patents describe a system where reactions carried out in a test tube in the laboratory can be used directly, without substantially modifying the composition of the reagents. Furthermore, certain tests which do not produce a change in absorbance, fluorescence or reflectance, such as with ion specific electrodes cannot be applied directly to the systems described in the aforementioned U.S. patents.